Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents

ABSTRACT

Combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant are shown to modulate each other&#39;s rate of release. Formulations of a therapeutically active agent and modulator provide substantially constant rate of release for an extended period of time.

TECHNICAL FIELD

Biodegradable implants formulated for controlled, sustained drugrelease.

BACKGROUND OF THE INVENTION

Solid pharmaceutically active implants that provide sustained release ofan active ingredient are able to provide a relatively uniformconcentration of active ingredients in the body. Implants areparticularly useful for providing a high local concentration at aparticular target site for extended periods of time. These sustainedrelease forms reduce the number of doses of the drug to be administered,and avoid the peaks and troughs of drug concentration found withtraditional drug therapies. Use of a biodegradable drug delivery systemhas the further benefit that the spent implant need not be removed fromthe target site.

Many of the anticipated benefits of delayed release implants aredependent upon sustained release at a relatively constant level.However, formulations of hydrophobic drugs with biodegradable matricesmay have a release profile which shows little or no release untilerosion of the matrix occurs, at which point there is a dumping of drug.

The eye is of particular interest when formulating implantable drugs,because one can reduce the amount of surgical manipulation required, andprovide effective levels of the drug specifically to the eye. When asolution is injected directly into the eye, the drug quickly washes outor is depleted from within the eye into the general circulation. Fromthe therapeutic standpoint, this may be as useless as giving no drug atall. Because of this inherent difficulty of delivering drugs into theeye, successful medical treatment of ocular diseases is inadequate.

Improved sustained release formulations which allow for a constant drugrelease rate are of considerable interest for medical and veterinaryuses.

Relevant Literature

U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biocompatible implantsfor introducing into an anterior chamber or posterior segment of an eyefor the treatment of an ocular condition.

Heller, Biodegradable Polymers in Controlled Drug Delivery, in: CRCCritical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press,Boca Raton, Fla., 1987, pp 39-90, describes encapsulation for controlleddrug delivery. Heller in: Hydrogels in Medicine and Pharmacy, N. A.Peppes ed., Vol. III, CRC Press, Boca Raton, Fla., 1987, pp 137-149,further describes bioerodible polymers.

Anderson et al., Contraception (1976) 13:375 and Miller et al., J.Biomed. Materials Res. (1977) 11:711, describe various properties ofpoly(dL-lactic acid). U.S. Pat. No. 5,075,115 discloses sustainedrelease formulations with lactic acid polymers and co-polymers.

Di Colo (1992) Biomaterials 13:850-856 describes controlled drug releasefrom hydrophobic polymers.

SUMMARY OF THE INVENTION

Compositions and methods are provided for biodegradable implantsformulated to provide a controlled, sustained drug release. The releaserate is modulated by combining in the implant hydrophobic andhydrophilic agents. The release modulator may act to accelerate orretard the rate of release. Optionally, the modulator will be atherapeutically active agent. The invention provides a sustained releaseimplant having a combination of active agents with a defined releaseprofile.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the release profile of a hydrophobic drug from an extendedrelease drug delivery system. FIG. 1B shows the release profile of thesame drug when formulated in a drug delivery system with a releasemodulator.

FIG. 2A shows the release profile of dexamethasone in the absence orpresence of the release modifier, ciproflaxacin HCl. FIG. 2B shows therelease of ciprofloxacin in the presence of dexamethasone. FIG. 2C showsthe release of ciprofloxacin in the absence of a release modifier. FIG.2D shows the releae profile from a drug delivery system having combinedhydrophilic and hydrophobic drugs, and further having a pharmaceuticallyinactive release modifier.

FIG. 3 shows a cross-sectional view of an eye.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

A controlled drug release is achieved by an improved formulation of slowrelease biodegradable implants. The release rate of a drug from animplant is modulated by addition of a release modulator to the implant.Release of a hydrophobic agent is increased by inclusion of anaccelerator in the implant, while retardants are included to decreasethe release rate of hydrophilic agents. The release modulator may bephysiologically inert, or a therapeutically active agent.

The rate of release of the therapeutically active agent will becontrolled by the rate of transport through the polymeric matrix of theimplant, and the action of the modulator. By modulating the releaserate, the agent is released at a substantially constant rate, or withina therapeutic dosage range, over the desired period of time. The rate ofrelease will usually not vary by more than about 100% over the desiredperiod of time, more usually by not more than about 50%. The agent ismade available to the specific site(s) where the agent is needed, and itis maintained at an effective dosage. The transport of drug through thepolymer barrier will also be affected by drug solubility, polymerhydrophilicity, extent of polymer cross-linking, expansion of thepolymer upon water absorption so as to make the polymer barrier morepermeable to the drug, geometry of the implant, and the like.

The release modulator is an agent that alters the release of a drug froma biodegradable implant in a defined manner. It may be an accelerator ora retardant. Accelerators will be hydrophilic compounds, which are usedin combination with hydrophobic agents to increase the rate of release.Hydrophilic agents are those compounds which have at least about 100μg/ml solubility in water at ambient temperature. Hydrophobic agents arethose compounds which have less than about 100 μg/ml solubility in waterat ambient temperature.

Therapeutically active hydrophobic agents which benefit from releasemodulation include cyclosporines, e.g. cyclosporin A, cyclosporin G,etc.; vinca alkaloids, e.g. vincristine and vinblastine; methotrexate;retinoic acid; certain antibiotics, e.g. ansamycins such as rifampin;nitrofurans such as nifuroxazide; non-steroidal antiinflammatory drugs,e.g. diclofenac, keterolac, flurbiprofen, naproxen, suprofen, ibuprofen,aspirin, etc. Steroids are of particular interest, includinghydrocortisone, cortisone, prednisolone, prednisone, dexamethasone,medrysone, fluorometholone, estrogens, progesterones, etc.

Accelerators may be physiologically inert, water soluble polymers, e.g.low molecular weight methyl cellulose or hydroxypropyl methyl cellulose(HPMC); sugars, e.g. monosaccharides such as fructose and glucose,disaccharides such as lactose, sucrose, or polysaccharides such ascellulose, amylose, dextran, etc. Alternatively, the accelerator may bea physiologically active agent, allowing for a combined therapeuticformulation. The choice of accelerator in such a case will be determinedby the desired combination of therapeutic activities.

Formulations of particular interest will have a therapeutic combinationof two or more active agents, which provides for a sustained release ofthe agents. Combinations may include steroids, as indicated above, asthe hydrophobic agent and water soluble antibiotics, e.g.aminoglycosides such as gentamycin, kanamycin, neomycin, and vancomycin;amphenicols such as chloramphenicol; cephalosporins, such as cefazolinHCl; penicillins such as ampicillin, penicillin, carbenicillin,oxycillin, methicillin; lincosamides such as lincomycin; polypeptideantibiotics such as polymixin and bacitracin; tetracyclines such astetracycline; quinolones such as ciproflaxin, etc.; sulfonamides such aschloramine T; and sulfones such as sulfanilic acid as the hydrophilicentity. A combination of non-steroidal anti-inflammatory drugs, asindicated above, with water soluble antibiotics is also of interest.Combinations of anti-viral drugs, e.g. acyclovir, gancyclovir,vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine withsteroidal or non-steroidal anti-inflammatory drugs, as indicated above,are of interest. A particular combination of interest is dexamethasoneand ciproflaxin.

Release retardants are hydrophobic compounds which slow the rate ofrelease of hydrophilic drugs, allowing for a more extended releaseprofile. Hydrophilic drugs of interest which may benefit from releasemodulation include water soluble antibiotics, as described above,nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine,azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine;isoflurphate; adriamycin; bleomycin; mitomycin; ara-C; actinomycin D;scopolamine; and the like.

Agents of interest as release retardants include non-water solublepolymers, e.g. high molecular weight methylcellulose and ethylcellulose,etc., low water soluble organic compounds, and pharmaceutically activehydrophobic agents, as previously described.

A combined anti-inflammatory drug, and antibiotic or antiviral, may befurther combined with an additional therapeutic agent. The additionalagent may be an analgesic, e.g. codeine, morphine, keterolac, naproxen,etc., an anesthetic, e.g. lidocaine; β-adrenergic blocker orβ-adrenergic agonist, e.g. ephidrine, epinephrine, etc.; aldosereductase inhibitor, e.g. epalrestat, ponalrestat, sorbinil, tolrestat;antiallergic, e.g. cromolyn, beclomethasone, dexamethasone, andflunisolide; colchicine. Anihelminthic agents, e.g. ivermectin andsuramin sodium; antiamebic agents, e.g. chloroquine andchlortetracycline; and antifungal agents, e.g. amphotericin, etc. may beco-formulated with an antibiotic and an anti-inflammatory drug. Forintra-ocular use, anti-glaucomas agents, e.g. acetozolamide, befunolol,etc. in combinations with anti-inflammatory and antimicrobial agents areof interest. For the treatment of neoplasia, combinations withanti-neoplastics, particularly vinblastine, vincristine, interferons α,β and γ, antimetabolites, e.g. folic acid analogs, purine analogs,pyrimidine analogs may be used. Immunosuppressants such as azathiprine,cyclosporine and mizoribine are of interest in combinations. Also usefulcombinations include miotic agents, e.g. carbachol, mydriatic agentssuch as atropine, etc., protease inhibitors such as aprotinin, camostat,gabexate, vasodilators such as bradykinin, etc., and various growthfactors, such epidermal growth factor, basic fibroblast growth factor,nerve growth factors, and the like.

The amount of active agent employed in the implant, individually or incombination, will vary widely depending on the effective dosage requiredand rate of release from the implant. Usually the agent will be at leastabout 1, more usually at least about 10 weight percent of the implant,and usually not more than about 80, more usually not more than about 40weight percent of the implant. The amount of release modulator employedwill be dependent on the desired release profile, the activity of themodulator, and on the release profile of the active agent in the absenceof modulator. An agent that is released very slowly or very quickly willrequire relatively high amounts of modulator. Generally the modulatorwill be at least 10, more usually at least about 20 weight percent ofthe implant, and usually not more than about 50, more usually not morethan about 40 weight percent of the implant.

Where a combination of active agents is to be employed, the desiredrelease profile of each active agent is determined. If necessary, aphysiologically inert modulator is added to precisely control therelease profile. The drug release will provide a therapeutic level ofeach active agent.

The exact proportion of modulator and active agent will be empiricallydetermined by formulating several implants having varying amounts ofmodulator. A USP approved method for dissolution or release test will beused to measure the rate of release (USP 23; NF 18 (1995) pp.1790-1798). For example, using the infinite sink method, a weighedsample of the drug delivery device is added to a measured volume of asolution containing four parts by weight of ethanol and six parts byweight of deionized water, where the solution volume will be such thatthe drug concentration is after release is less than 5% of saturation.The mixture is maintained at 37° C. and stirred slowly to maintain theimplants in suspension. The appearance of the dissolved drug as afunction of time may be followed by various methods known in the art,such as spectrophotometrically, HPLC, mass spectroscopy, etc. until theabsorbance becomes constant or until greater than 90% of the drug hasbeen released. The drug concentration after 1 h in the medium isindicative of the amount of free unencapsulated drug in the dose, whilethe time required for 90% drug to be released is related to the expectedduration of action of the dose in vivo. Normally the release will befree of larger fluctuations from some average value which allows for arelatively uniform release, usually following a brief initial phase ofrapid release of the drug.

Normally the implant will be formulated to release the active agent(s)over a period of at least about 3 days, more usually at least about oneweek, and usually not more than about one year, more usually not morethan about three months. For the most part, the matrix of the implantwill have a physiological lifetime at the site of implantation at leastequal to the desired period of administration, preferably at least twicethe desired period of administration, and may have lifetimes of 5 to 10times the desired period of administration. The desired period ofrelease will vary with the condition that is being treated. For example,implants designed for post-cataract surgery will have a release periodof from about 3 days to 1 week; treatment of uveitis may require releaseover a period of about 4 to 6 weeks; while treatment for cytomegalovirusinfection may require release over 3 to 6 months, or longer.

The implants are of dimensions commensurate with the size and shape ofthe region selected as the site of implantation and will not migratefrom the insertion site following implantation. The implants will alsopreferably be at least somewhat flexible so as to facilitate bothinsertion of the implant at the target site and accommodation of theimplant. The implants may be particles, sheets, patches, plaques,fibers, microcapsules and the like and may be of any size or shapecompatible with the selected site of insertion.

The implants may be monolithic, i.e. having the active agenthomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix. Due to ease of manufacture, monolithic implants are usuallypreferred over encapsulated forms. However, the greater control affordedby the encapsulated, reservoir-type may be of benefit in somecircumstances, where the therapeutic level of the drug falls within anarrow window. The selection of the polymeric composition to be employedwill vary with the site of administration, the desired period oftreatment, patient tolerance, the nature of the disease to be treatedand the like. Characteristics of the polymers will includebiodegradability at the site of implantation, compatibility with theagent of interest, ease of encapsulation, a half-life in thephysiological environment of at least 7 days, preferably greater thantwo weeks, water insoluble, and the like. The polymer will usuallycomprise at least about 10, more usually at least about 20 weightpercent of the implant.

Biodegradable polymeric compositions which may be employed may beorganic esters or ethers, which when degraded result in physiologicallyacceptable degradation products, including the monomers. Anhydrides,amides, orthoesters or the like, by themselves or in combination withother monomers, may find use. The polymers will be condensationpolymers. The polymers may be cross-linked or non-cross-linked, usuallynot more than lightly cross-linked, generally less than 5%, usually lessthan 1%. For the most part, besides carbon and hydrogen, the polymerswill include oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen may be present as amide, cyano and amino. The polymers setforth in Heller, supra, may find use, and that disclosure isspecifically incorporated herein by reference.

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. By employing the L-lactate or D-lactate, a slowly biodegradingpolymer is achieved, while degradation is substantially enhanced withthe racemate. Copolymers of glycolic and lactic acid are of particularinterest, where the rate of biodegradation is controlled by the ratio ofglycolic to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic and lactic acid, where either homopolymer ismore resistant to degradation. The ratio of glycolic acid to lactic acidwill also affect the brittleness of in the implant, where a moreflexible implant is desirable for larger geometries.

Among the polysaccharides will be calcium alginate, and functionalizedcelluloses, particularly carboxymethylcellulose esters characterized bybeing water insoluble, a molecular weight of about 5 kD to 500 kD, etc.Biodegradable hydrogels may also be employed in the implants of thesubject invention. Hydrogels are typically a copolymer material,characterized by the ability to imbibe a liquid. Exemplary biodegradablehydrogels which may be employed are described in Heller in: Hydrogels inMedicine and Pharmacy, N. A. Peppes ed., Vol. III, CRC Press, BocaRaton, Fla., 1987, pp 137-149.

Particles can be prepared where the center may be of one material andthe surface have one or more layers of the same or differentcomposition, where the layers may be cross-linked, of differentmolecular weight, different density or porosity, or the like. Forexample, the center would comprise a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Most ratios of lactate to glycolate employed willbe in the range of about 1:0.1 to 1:1. Alternatively, the center couldbe polyvinyl alcohol coated with polylactate, so that on degradation ofthe polylactate the center would dissolve and be rapidly washed out ofthe implantation site.

The formulation of implants for use in the treatment of ocularconditions, diseases, tumors and disorders are of particular interest.The biodegradable implants may be implanted at various sites, dependingon the shape and formulation of the implant, the condition beingtreated, etc. Suitable sites include the anterior chamber, posteriorchamber, vitreous cavity, suprachoroidal space, subconjunctiva,episcleral, intracorneal, epicorneal and sclera. Suitable sitesextrinsic to the vitreous comprise the suprachoroidal space, the parsplana and the like. The suprachoroid is a potential space lying betweenthe inner scleral wall and the apposing choroid. Implants that areintroduced into the suprachoroid may deliver drugs to the choroid and tothe anatomically apposed retina, depending upon the diffusion of thedrug from the implant, the concentration of drug comprised in theimplant and the like. Implants may be introduced over or into anavascular region. The avascular region may be naturally occurring, suchas the pars plana, or a region made to be avascular by surgical methods.Surgically-induced avascular regions may be produced in an eye bymethods known in the art such as laser ablation, photocoagulation,cryotherapy, heat coagulation, cauterization and the like. It may beparticularly desirable to produce such an avascular region over or nearthe desired site of treatment, particularly where the desired site oftreatment is distant from the pars plana or placement of the implant atthe pars plana is not possible. Introduction of implants over anavascular region will allow for diffusion of the drug from the implantand into the inner eye and avoids diffusion of the drug into thebloodstream.

Turning now to FIG. 3, a cross-sectional view of the eye is shown,illustrating the sites for implantation in accordance with the subjectinvention. The eye comprises a lens 16 and encompasses the vitreouschamber 3. Adjacent to the vitreous chamber 3 is the optic part of theretina 11. Implantation may be intraretinal 11 or subretinal 12. Theretina is surrounded by the choroid 18. Implantation may beintrachoroidal or suprachoroidal 4. Between the optic part of the retinaand the lens, adjacent to the vitreous, is the pars plana 19.Surrounding the choroid 18 is the sclera 8. Implantation may beintrascleral 8 or episcleral 7. The external surface of the eye is thecornea 9. Implantation may be epicorneal 9 or intra-corneal 10. Theinternal surface of the eye is the conjunctiva 6. Behind the cornea isthe anterior chamber 1, behind which is the lens 16. The posteriorchamber 2 surrounds the lens, as shown in the figure. Opposite from theexternal surface is the optic nerves, and the arteries and vein of theretina. Implants into the meningeal spaces 13, the optic nerve 15 andthe intraoptic nerve 14 allows for drug delivery into the centralnervous system, and provide a mechanism whereby the blood-brain barriermay be crossed.

Other sites of implantation include the delivery of anti-tumor drugs toneoplastic lesions, e.g. tumor, or lesion area, e.g. surroundingtissues, or in those situations where the tumor mass has been removed,tissue adjacent to the previously removed tumor and/or into the cavityremaining after removal of the tumor. The implants may be administeredin a variety of ways, including surgical means, injection, trocar, etc.

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Water soluble preservatives which may be employed includesodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. These agents may be present in individual amounts of from about0.001 to about 5% by weight and preferably about 0.01 to about 2%.Suitable water soluble buffering agents that may be employed are sodiumcarbonate, sodium borate, sodium phosphate, sodium acetate, sodiumbicarbonate, etc., as approved by the FDA for the desired route ofadministration. These agents may be present in amounts sufficient tomaintain a pH of the system of between 2 to 9 and preferably 4 to 8. Assuch the buffering agent may be as much as 5% on a weight to weightbasis of the total composition. Where the buffering agent or enhancer ishydrophilic, it may also act as a release accelerator, and may replaceall or part of the hydrophilic agent. Similarly, a hydrophilic bufferingagent or enhance may replace all or part of the hydrophobic agent.

The implants may be of any geometry including fibers, sheets, films,microspheres, circular discs, plaques and the like. The upper limit forthe implant size will be determined by factors such as toleration forthe implant, size limitations on insertion, ease of handling, etc. Wheresheets or films are employed, the sheets or films will be in the rangeof at least about 0.5 mm×0.5 mm, usually about 3-10 mm×5-10 mm with athickness of about 0.25-1.0 mm for ease of handling. Where fibers areemployed, the diameter of the fiber will generally be in the range of0.05 to 3 mm. The length of the fiber will generally be in the range of0.5-10 mm. Spheres will be in the range of 2 μm to 3 mm in diameter.

The size and form of the implant can be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. Larger implants will deliver a proportionately largerdose, but depending on the surface to mass ratio, may have a slowerrelease rate. The particular size and geometry of an implant will bechosen to best suit the site of implantation. The chambers, e.g.anterior chamber, posterior chamber and vitreous chamber, are able toaccomodate relatively large implants of varying geometries, havingdiameters of 1 to 3 mm. A sheet, or circular disk is preferable forimplantation in the suprachoroidal space. The restricted space forintraretinal implantation requires relatively small implants, havingdiameters from 0.5 to 1 mm.

In some situations mixtures of implants may be utilized employing thesame or different pharmacological agents. In this way, a cocktail ofrelease profiles, giving a biphasic or triphasic release with a singleadministration is achieved, where the pattern of release may be greatlyvaried.

Various techniques may be employed to produce the implants. Usefultechniques include solvent evaporation methods, phase separationmethods, interfacial methods, extrusion methods, molding methods,injection molding methods, heat press methods and the like. Specificmethods are discussed in U.S. Pat. No. 4,997,652, herein incorporated byreference. In a preferred embodiment, extrusion methods are used toavoid the need for solvents in manufacturing. When using extrusionmethods, the polymer and drug are chosen so as to be stable at thetemperatures required for manufacturing, usually at least about 85° C.

The following examples are offered by way of illustration and not by wayof limitation.

EXPERIMENTAL Example 1

Manufacture and Testing of a Drug Delivery System (DDS) without aRelease Modulator

Release of the hydrophobic drug dexamethasone from an extended releasedrug delivery system was measured. The drug delivery system was madewith dexamethasone and polylactic acid/polyglycolic acid copolymer.Dexamethasone powder and a powder of polylactic acid polyglycolic acid(PLGA) copolymer were mixed throughly at a ratio of 50/50. The wellmixed powder was filled into an extruder, and heated for 1 hour at 95°C., then extruded through a 20 gauge orifice. Six DDS of approximately100-120 μg were cut from the extruded filaments for drug releaseassessment.

Each individual DDS was placed in a glass vial filled with receptormedium (9% NaCl in water). To allow for “infinite sink” conditions, thereceptor medium volume was chosen so that the concentration would neverexceed 5% of saturation. To minimize secondary transport phenomena, e.g.concentration polarization in the stagnant boundary layer, each of theglass vials was placed into a shaking water bath at 37° C. Samples weretaken for HPLC analysis from each vial at defined time points. The HPLCmethod was as described in USP 23 (1995) pp. 1791-1798. Theconcentration values were used to calculate the cumulative relaseprofiles. The release profile is shown in FIG. 1A. It is seen that drugrelease is very slow with this DDS. Appreciable drug release begins inthe fourth week after initiation, at approximately the time of polymerdisintegration.

Manufacture and Testing of a DDS with HPMC Release Modifier

A drug delivery system was manufactured as described above, except thatvarious concentrations of hydrophilic hydroxypropylmethylcellulose(HPMC) were included as a release modifier. The combinations of drug,polymer and HPMC shown in Table 1 were used. TABLE 1 Lot # PLGA HPMCDexamethasone Total XT014 3.5 1.5 5 10 XT015 2 2 5 9 XT013 1.5 1.5 5 8

The release of drug was tested as described above. The data is shown inFIG. 1B. It is seen that with the addition of HPMC, there is apronounced increase in the rate of release. Close to zero order releaseis observed for XT014 and XT015, where the ratio of release modulator todrug is 0.3 to 0.4. By selection of the appropriate polymer and releasemodifier, drug release and delivery interval can be custom-tailored toprovide a release profile that is accelerated or retarded.

Example 2

Manufacture and Testing of A DDS with a Pharmaceutically Active ReleaseModifier

A drug delivery system was manufactured as described in Example 1,except that ciprofloxacin HCl, a pharmaceutically active, hydrophiliccompound, was included as a release modifier. The combinations of drug,polymer and HPMC shown in Table 2 were used. TABLE 2 Release Lot # PLGAModifier Drug XT029 5 — 5 dexamethasone XT032 4 2 ciprofloxacin 4dexamethasone XT030 5 — 5 ciprofloxacin

The release of dexamethasone is increased with the addition ofciprofloxacin HCl, as shown by the data in FIG. 2A. The actual drugrelease is almost doubled when compared to the DDS without a modifier.In addition to the benefits of increased drug delivery, there aretherapeutic benefits introduced with the antibiotic activity ofciprofloxacin. The release of ciprofloxacin from from the same DDS isshown in FIG. 2B. The release rate is higher than that of dexamethasone.However, the overall release of ciprofloxacin is slower whenco-formulated with dexamethasone than it is without dexamethasone, asshown in FIG. 2C.

Example 3

Manufacture and Testing of A DDS with Multiple Release Modifiers

A drug delivery system was formulated with hydroxymethylcellulose,cirpofloxacin HCl and dexamethasone, according to the Table 3. TABLE 3Lot # PLGA HPMC Ciprofloxacin Dexamethasone XT035 3.4 0.4 2.4 3.8The data show that after an initial higher release in the first day, analmost zero-order release there after can be observed. The overallrelease characteristic would be therapeutically acceptable from atherapeutic efficiency aspect.

It is evident from the above results that biodegradable implantsformulated with an active agent and release modulator provide forrelease kinetics where the drug is released at a constant rate over longperiods of time, avoiding the need of a patient to administer drugs inmuch less effective ways, such as topically. The implants provide animproved method of treating ocular and other conditions, by avoidingpeaks and troughs of drug release.

All publications and patent applications mentioned in this specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

1-9. (Canceled)
 10. A biodegradable implant for placement in an eye,comprising: a steroid and a polylactic acid polyglycolic acid (PLGA)copolymer, wherein the steroid makes up between about 1 percent byweight and about 80 percent by weight of the implant, and wherein theimplant releases at least about 10% of the steroid within 1 week. 11.The implant of claim 10, wherein the steroid is dexamethasone.
 12. Theimplant of claim 11, wherein the dexamethasone makes up about 50 percentby weight of the implant.
 13. The implant of claim 10, wherein thesteroid is located within a polylactic acid polyglycolic acid (PLGA)copolymer matrix.
 14. The implant of claim 10, wherein the implantreleases at least about 10% of the steroid within 1 week when measuredunder infinite sink condition in vitro.
 15. The implant of claim 10,wherein the implant releases at least about 20% of the steroid withinabout 3 weeks when measured under infinite sink conditions in vitro. 16.The implant of claim 10, wherein the implant releases at least about 60%of the steroid within about 4 weeks when measured under infinite sinkconditions in vitro.
 17. The implant of claim 10, which includes norelease modifier.
 18. The implant of claim 10, wherein the copolymer iseffective in controlling the release of the steroid from the implant.19. A biodegradable implant for placement in an eye, comprising: anextruded mixture of a steroid and a biodegradable polylactic acidpolyglycolic acid (PLGA) copolymer, wherein the steroid makes up betweenabout 1 percent by weight and about 80 percent by weight of thebiodegradable implant.
 20. The implant of claim 19, wherein the steroidis dexamethasone.
 21. The implant of claim 19, which includes no releasemodifier.
 22. The implant of claim 19, wherein the copolymer iseffective in controlling the release of the steroid from the implant.